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Mechanisms of Pol II Elongation in Diffuse Midline Glioma

Award Number: R01NS129860
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Mechanisms of Pol II Elongation in Diffuse Midline Glioma - Project Summary/Abstract Diffuse midline gliomas (DMGs) are aggressive brain tumors in both children and adults with no effective therapies. Over 80% of pediatric DMG and a majority of adult DMG harbor non-synonymous mutations in histone H3 (H3.3K27M and H3.1K27M), which dysregulate chromatin and result in aberrant Pol II transcription in brain tumors compared to normal tissue. Aberrant transcription is not only a cause of tumorigenesis, but also a druggable vulnerability as there are multiple studies investigating the utility of Pol II and epigenome-targeting drugs for the treatment of cancer. Despite the initial promise of compounds targeting transcriptional dysregulation as potential cancer therapies, none of the drugs under investigation in clinical trials have improved DMG patient survival thus far. A critical barrier to the discovery of more effective and less toxic therapies for DMG is our lack of functional knowledge regarding the molecular pathways connecting H3K27M mutant histones to tumor initiation and progression. We have recently conducted CRISPR screens identifying multiple regulators of Pol II transcriptional elongation as genetic dependencies in H3K27M mutant cells, including Elongin B (ELOB), and its binding partner, the Von Hippel-Lindau disease protein and tumor suppressor, VHL. Further preliminary studies reveal that genetic ablation of ELOB alters the chromatin binding patterns of H3K27M mutant histones, and disrupts DMG gene expression. These data support our overall hypothesis that H3K27M mutant histones enlist the activity of specific gene regulatory complexes to induce Pol II transcriptional deregulation and trigger DMG tumorigenesis. Our broad, long-term goal is to identity genes and molecular pathways driving glioma-specific transcriptional programs and to determine their roles in brain cancer development and progression. We propose the following specific aims: 1) Establish roles for Pol II elongation regulators in pre-clinical mouse models of DMG and investigate genetic interactions between the elongation machinery and H3K27M; 2) Apply cutting edge next generation sequencing analyses to dissect mechanisms of crosstalk between Pol II regulatory proteins and H3K27M and determine their roles in promoting abnormal gene regulation in DMG; 3) Investigate an unexpected oncogenic role for Elongin/VHL complexes in promoting malignant gene expression patterns and DMG tumor growth. The significance of this work is that these studies will reveal new insights into how H3K27M oncogenic histones co-opt specific Pol II regulators to promote tumorigenesis, and will uncover molecular mechanisms driving aberrant chromatin and gene regulation in DMG and other cancers.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $419,551 )
2026	2026	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/22/2026	NON-COMPETING CONTINUATION	$419,551
														Subtotal = $419,551

Issue Date FY: 2025 ( Subtotal = $419,551 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/17/2025	NON-COMPETING CONTINUATION	$419,551
														Subtotal = $419,551

Issue Date FY: 2024 ( Subtotal = $457,561 )
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/26/2024	NON-COMPETING CONTINUATION	$424,543
2024	2024	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/3/2024	NON-COMPETING CONTINUATION	$33,018
														Subtotal = $457,561

Issue Date FY: 2023 ( Subtotal = $473,032 )
2023	2023	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	2/3/2023	NEW	$473,032
														Subtotal = $473,032

Grand Total All Awards = $1,769,695

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Mechanisms of Pol II Elongation in Diffuse Midline Glioma

Award Number: R01NS129860

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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